Sudden cardiac arrest (SCA) is a leading cause of death in the United States. It affects over 500,000 people annually with an overall survival rate of 7%. Unlike other leading causes of death, no pharmacological drugs exist to improve SCA survival. Cooling a few degrees Celsius during cardiopulmonary resuscitation (CPR) in pre-clinical studies is highly protective against SCA injury and appears mediated by enhanced Akt signaling. However, CPR cooling is difficult to physically implement clinically. Development of new CPR drugs that mimic cooling protection without the need for physical cooling could be highly effective and translational. Proposed work uses two novel cell-permeable peptides designed to inhibit PHLPP phosphatase (TAT-PHLPP9c) and to activate PDK1 (TAT-PIF) respectively. They reach critical organs such as heart and brain in less than 5 min when administering to the mouse intravenously and synergistically improve 4 h SCA survival after prolonged 12 min asystole cardiac arrest. Preliminary work in swine demonstrates that intravenous administration of TAT- PHLPP9c during CPR rapidly improves recovery of cardiac function after ROSC and significantly improves 24 hour neurologically intact survival after 5 min ventricular defibrillation (VF). We hypothesize that CPR administration of TAT-PHLPP9c and TAT-PIF collaboratively induce a rapid and maximal activation of Akt, subsequently enhances PDH activity, reduces glucose shunting to sorbitol, and enhances glucose utilization leading to an early replenishment of energy, diminished osmotic injury and release of taurine and glutamate into blood, and improved cardiac function and neurologically intact survival. This proposal will take systematic efforts to test a novel therapeutic strategy and their mechanisms of action by intravenously administration of cell-permeable peptides (TAT-PHLPP9c and TAT-PIF) during CPR following cardiac arrest in mouse, and swine, and further validate biomarkers and a non-invasive measurement of optic nerve sheath diameter (ONSD) to predict SCA outcome in human as illustrated in the following three aims. Aim 1. Determine whether TAT-PHLPP9c, a novel biological inhibitor of PHLPP phosphatase, and TAT-PIF, a novel biological activator of PDK1, improves SCA survival in a prolonged arrest (12 min) mouse SCA model. Aim 2. Determine whether these novel peptides improve swine SCA survival when given intravenously during CPR and compare the efficacy of these peptides to active cooling and ECMO therapies for SCA. Aim 3. Test biomarkers (taurine and glutamate) of osmotic stress and metabolic recovery with ultrasound measurement of osmotic stress-related ONSD to predict SCA outcome. Swine and human have a number of similarities in anatomy and physiology, therefore swine has been widely accepted as a highly translational model in testing therapies. If these two peptides can work as cooling and bring dead swine back after SCA, they have a high possibility to work in the human as cooling without a need to physically cool the patients which would be a major advance in SCA resuscitation.